Acetic Acid → (3S,5S)-5-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-ylmethyl)-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester

HRID 1261845Notes

Reaction equation

HRID 1261845 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH:15]2[O:16][CH2:17][CH2:18][CH2:19][C@@H:20]([CH2:21]O)[N:14]2[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.Cl.[CH2:39]1[C:41]2([CH2:46][CH2:45][NH:44][CH2:43][C@H:42]2[OH:47])[CH2:40]1.CCN(CC)CC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH:15]2[O:16][CH2:17][CH2:18][CH2:19][C@@H:20]([CH2:21][N:44]3[CH2:45][CH2:46][C:41]4([CH2:39][CH2:40]4)[C@H:42]([OH:47])[CH2:43]3)[N:14]2[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 6909Trichloroisocyanuric AcidHCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochlorideHCID 67093093(3S,5S)-5-hydroxymethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester

Product 1

HCID 67092932(3S,5S)-5-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-ylmethyl)-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl esterYield 52.8%

Reagents, catalysts & solvents 2

HCID 2724126TempoCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

2,2,6,6-Tetramethylpiperidine-1-oxyl radical (0.05 mg, 0.3 μmol) was added at room temperature to a suspension of (3S,5S)-5-hydroxymethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester (example 23B, 102 mg, 0.29 mmol) and trichloroisocyanuric acid (72 mg, 0.29 mmol) in DCM (1 mL), then after 5 min the mixture was washed with 1 M aq. sodium sulfite solution and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue [(3S,5S)-5-oxomethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester] was dissolved in DCM (1 mL) and added dropwise at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (48 mg, 0.29 mmol), Et3N (30 mg, 0.29 mmol), HOAc (35 mg, 0.58 mmol) and sodium triacetoxyborohydride (70 mg, 0.32 mmol) in DCM, then after 16 h the reaction mixture was cooled to 0° C. and partitioned between EtOAc and 1 M aq. sodium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced the title compound (70 mg, 52%). Light yellow gum, MS: 458.4 (M+H)+.

Workup

  1. washafter 5 min the mixture was washed with 1 M aq. sodium sulfite solution and brine
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated
  5. dissolutionThe residue [(3S,5S)-5-oxomethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester] was dissolved in DCM (1 mL)
  6. custompartitioned between EtOAc and 1 M aq. sodium carbonate solution
  7. washThe organic layer was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. customevaporated

Sources & evidence

ORD record
ord-5b354d680c5e4dedae8d84b3ab76ffa1
Source dataset
uspto-grants-2013_06
Patent number
US08471004B2

Reaction notes

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